As people are now aging with HIV-infection, there is evidence that the cumulative incidence of HAND is continuing to increase 8-12. It is not currently understood why some HIV-infected individuals develop cognitive impairments while others do not. Likewise, there are no biological measures that can identify individuals with asymptomatic neurocognitive impairments (ANI) who are likely to progress to more severe forms of cognitive impairments including mild neurocognitive disorder (MND) or frank dementia (HIV associated dementia; HAD), or who is likely to spontaneously improve. The objective of this proposal is to use combinational informatics approaches to identify neural systems that are perturbed early in the course of HAND, and to determine how longitudinal changes in neural systems are related to changes in cognitive function. These combined informatics approaches will break new ground in the molecular understanding of HAND that will aid in the development new classes of neuroprotective drugs. These approaches are also likely to pinpoint a unique set of surrogate markers that may identify HIV infected individuals at a prodromal phase of HAND, when neuroprotective therapeutic intervention would have the greatest benefit. To accomplish these goals we propose to use a combinational informatics systems approach to interrogate a unique set of clinical samples that have undergone extensive analysis at multiple performance sites.